Discovery of Novel Inhibitor Scaffolds against the Metallo-β-lactamase VIM-2 by Surface Plasmon Resonance (SPR) Based Fragment Screening
| Autor: | Hanna-Kirsti S. Leiros, Trine Josefine Olsen Carlsen, Ronny Helland, Tony Christopeit |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Stereochemistry Drug resistance Crystallography X-Ray beta-Lactamases Metallo β lactamase Small Molecule Libraries Carbapenem Antibiotics Drug Resistance Bacterial Drug Discovery Ic50 values Humans Pseudomonas Infections Surface plasmon resonance Drug discovery Chemistry Surface Plasmon Resonance VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Legemiddelkjemi: 448 bacterial infections and mycoses Ligand (biochemistry) Combinatorial chemistry Carbapenems Drug Design Pseudomonas aeruginosa Molecular Medicine beta-Lactamase Inhibitors Function (biology) |
| Zdroj: | Journal of Medicinal Chemistry. 58:8671-8682 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.5b01289 |
| Popis: | Accepted manuscript version. Published version at http://doi.org/10.1021/acs.jmedchem.5b01289. Metallo-β-lactamase (MBL) inhibitors can restore the function of carbapenem antibiotics and therefore help to treat infections of antibiotic resistant bacteria. In this study, we report novel fragments inhibiting the clinically relevant MBL Verona integron-encoded metallo-β-lactamase (VIM-2). The fragments were identified from a library of 490 fragments using an orthogonal screening approach based on a surface plasmon resonance (SPR) based assay combined with an enzyme inhibition assay. The identified fragments showed IC50 values between 14 and 1500 μM and ligand efficiencies (LE) between 0.48 and 0.23 kcal/mol per heavy atom. For two of the identified fragments, crystal structures in complex with VIM-2 were obtained. The identified fragments represent novel inhibitor scaffolds and are good starting points for the design of potent MBL inhibitors. Furthermore, the established SPR based assay and the screening approach can be adapted to other MBLs and in this way improve the drug discovery process for this important class of drug targets. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|